A new way to regulate protein levels and functions could be the answer to treating devastating neurological conditions
New details learned about a key cellular protein could lead to treatments for neurodegenerative diseases, such as Parkinson’s, Huntington’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS).
At their root, these disorders are triggered by misbehaving proteins in the brain. The proteins misfold and accumulate in neurons, inflicting damage and eventually killing the cells. In a new study, researchers in the laboratory of Steven Finkbeiner, MD, PhD, at the Gladstone Institutes used a different protein, Nrf2, to restore levels of the disease-causing proteins to a normal, healthy range, thereby preventing cell death.
The researchers tested Nrf2 in two models of Parkinson’s disease: cells with mutations in the proteins LRRK2 and a-synuclein. By activating Nrf2, the researchers turned on several “house-cleaning” mechanisms in the cell to remove excess LRRK2 and ?-synuclein.
“Nrf2 coordinates a whole program of gene expression, but we didn’t know how important it was for regulating protein levels until now,” explained first author Gaia Skibinski, PhD, a staff research scientist at Gladstone. “Overexpressing Nrf2 in cellular models of Parkinson’s disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we’ve found.”
In the study, published in the Proceedings of the National Academy of Sciences, the scientists used both rat neurons and human neurons created from induced pluripotent stem cells. They then programmed the neurons to express Nrf2 and either mutant LRRK2 or a-synuclein. Using a one-of-a-kind robotic microscope developed by the Finkbeiner laboratory, the researchers tagged and tracked individual neurons over time to monitor their protein levels and overall health. They took thousands of images of the cells over the course of a week, measuring the development and demise of each one.
The scientists discovered that Nrf2 worked in different ways to help remove either mutant LRRK2 or ?-synuclein from the cells. For mutant LRRK2, Nrf2 drove the protein to gather into incidental clumps that can remain in the cell without damaging it. For a-synuclein, Nrf2 accelerated the breakdown and clearance of the protein, reducing its levels in the cell.
“I am very enthusiastic about this strategy for treating neurodegenerative diseases,” said Finkbeiner, a senior investigator at Gladstone and senior author on the paper. “We’ve tested Nrf2 in models of Huntington’s disease, Parkinson’s disease, and ALS, and it is the most protective thing we’ve ever found. Based on the magnitude and the breadth of the effect, we really want to understand Nrf2 and its role in protein regulation better.”
The scientists say that Nrf2 itself may be difficult to target with a drug because it is involved in so many cellular processes, so they are now focusing on some of its downstream effects. They hope to identify other players in the protein regulation pathway that interact with Nrf2 to improve cell health and that may be easier to drug.
Groundbreaking study demonstrates potential to help millions of people with disabilities
Researchers at the University of Minnesota have made a major breakthrough that allows people to control a robotic arm using only their minds. The research has the potential to help millions of people who are paralyzed or have neurodegenerative diseases.
The study is published online today in Scientific Reports, a Nature research journal.
“This is the first time in the world that people can operate a robotic arm to reach and grasp objects in a complex 3D environment using only their thoughts without a brain implant,” said Bin He, a University of Minnesota biomedical engineering professor and lead researcher on the study. “Just by imagining moving their arms, they were able to move the robotic arm.”
The noninvasive technique, called electroencephalography (EEG) based brain-computer interface, records weak electrical activity of the subjects’ brain through a specialized, high-tech EEG cap fitted with 64 electrodes and converts the “thoughts” into action by advanced signal processing and machine learning.
Eight healthy human subjects completed the experimental sessions of the study wearing the EEG cap. Subjects gradually learned to imagine moving their own arms without actually moving them to control a robotic arm in 3D space. They started from learning to control a virtual cursor on computer screen and then learned to control a robotic arm to reach and grasp objects in fixed locations on a table. Eventually, they were able to move the robotic arm to reach and grasp objects in random locations on a table and move objects from the table to a three-layer shelf by only thinking about these movements.
All eight subjects could control a robotic arm to pick up objects in fixed locations with an average success rate above 80 percent and move objects from the table onto the shelf with an average success rate above 70 percent.
“This is exciting as all subjects accomplished the tasks using a completely noninvasive technique. We see a big potential for this research to help people who are paralyzed or have neurodegenerative diseases to become more independent without a need for surgical implants,” He said.
The researchers said the brain-computer interface technology works due to the geography of the motor cortex—the area of the cerebrum that governs movement. When humans move, or think about a movement, neurons in the motor cortex produce tiny electric currents. Thinking about a different movement activates a new assortment of neurons, a phenomenon confirmed by cross-validation using functional MRI in He’s previous study. Sorting out these assortments using advanced signal processing laid the groundwork for the brain-computer interface used by the University of Minnesota researchers, He said.
The robotic arm research builds upon He’s research published three years ago in which subjects were able to fly a small quadcopter using the noninvasive EEG technology. The research gained international media attention.
“Three years ago, we weren’t sure moving a more complex robotic arm to grasp and move objects using this brain-computer interface technology could even be achieved,” He said. “We’re happily surprised that it worked with a high success rate and in a group of people.”
He anticipates the next step of his research will be to further develop this brain-computer interface technology realizing a brain-controlled robotic prosthetic limb attached to a person’s body or examine how this technology could work with someone who has had a stroke or is paralyzed.
Tiny magnetic particles from air pollution have for the first time been discovered to be lodged in human brains– and researchers think they could be a possible cause of Alzheimer’s disease.
Researchers at Lancaster University found abundant magnetite nanoparticles in the brain tissue from 37 individuals aged three to 92-years-old who lived in Mexico City and Manchester. This strongly magnetic mineral is toxic and has been implicated in the production of reactive oxygen species (free radicals) in the human brain, which are associated with neurodegenerative diseases including Alzheimer’s disease.
Professor Barbara Maher, from Lancaster Environment Centre, and colleagues (from Oxford, Glasgow, Manchester and Mexico City) used spectroscopic analysis to identify the particles as magnetite. Unlike angular magnetite particles that are believed to form naturally within the brain, most of the observed particles were spherical, with diameters up to 150 nm, some with fused surfaces, all characteristic of high-temperature formation – such as from vehicle (particularly diesel) engines or open fires.
The spherical particles are often accompanied by nanoparticles containing other metals, such as platinum, nickel, and cobalt.
Professor Maher said: “The particles we found are strikingly similar to the magnetite nanospheres that are abundant in the airborne pollution found in urban settings, especially next to busy roads, and which are formed by combustion or frictional heating from vehicle engines or brakes.”
Other sources of magnetite nanoparticles include open fires and poorly sealed stoves within homes. Particles smaller than 200 nm are small enough to enter the brain directly through the olfactory nerve after breathing air pollution through the nose.
“Our results indicate that magnetite nanoparticles in the atmosphere can enter the human brain, where they might pose a risk to human health, including conditions such as Alzheimer’s disease,” added Professor Maher.
Leading Alzheimer’s researcher Professor David Allsop, of Lancaster University’s Faculty of Health and Medicine, said: “This finding opens up a whole new avenue for research into a possible environmental risk factor for a range of different brain diseases.”
A team of researchers has built a mathematical model that describes the molecular events associated with the beginning stage of learning and memory formation in the human brain.
The research, published in the journal Proceedings of the National Academy of Sciences, paves the way for understanding cognitive function and neurodegenerative diseases—at the molecular and cellular levels.
The study focuses on the dynamics of dendritic spines, which are thorny structures that allow neurons to communicate with each other. When a spine receives a signal from another neuron, it responds by rapidly expanding in volume—an event called transient spine expansion.
Transient spine expansion is one of the early events leading up to learning and memory formation. It consists of a cascade of molecular processes spanning four to five minutes, beginning when a neuron sends a signal to another neuron.
Many of the molecular processes leading up to transient spine expansion have already been identified experimentally and reported in the literature. Here, the authors built a map of many of these known processes into a computational framework.
“Spines are dynamic structures, changing in size, shape and number during development and aging. Spine dynamics have been implicated in memory, learning and various neurodegenerative and neurodevelopmental disorders, including Alzheimer’s, Parkinson’s and autism. Understanding how the different molecules can affect spine dynamics can eventually help us demystify some of these processes in the brain,” said Padmini Rangamani, a mechanical engineering professor at the University of California San Diego and first author of the study.
“This work shows that dendritic spines, which are sub-micrometer compartments within individual neurons, are the prime candidates for the initial tag of transient, millisecond synaptic activity that eventually orchestrates memory traces in the brain lasting tens of years,” said Shahid Khan, senior scientist at the Molecular Biology Consortium at Lawrence Berkeley National Laboratory and a co-author on the PNAS paper.
In this study, researchers constructed a mathematical model, based on ordinary differential equations, linking the different molecular processes associated with spine expansion together. They identified the key components (molecules and enzymes) and chemical reactions that regulate spine expansion.
As a result, they observed an interesting pattern—that the same components could both turn on and off some of the steps in the sequence—a phenomenon called paradoxical signaling. Further, they linked the chemical reactions of the different molecules to the reorganization of the actin cytoskeleton, which gives the cell its shape.
Both of these features—paradoxical signaling and linking spine expansion to actin reorganization—make this model robust, Rangamani explained. “By putting all these complicated pieces together in a simple mathematical framework, we can start to understand the underlying mechanisms of spine expansion. This is one of the benefits of combining mechanics of the cytoskeleton and biochemistry. We can bring together pieces of experimental work that are often not seen. However, we should note that we are only at the beginning stages of understanding what spines, neurons and the brain can do.”
“This work is notable for bringing together aspects from diverse disciplines (systems biology, cell signaling, actin mechanobiology and proteomics) and should motivate similar multi-disciplinary efforts for other problems in fundamental cellular neuroscience,” Khan said.